tbuckley/cabot-search huggingface dataset:
CTNI-27. MULTI-CENTER, PHASE 2 STUDY EVALUATING THE PHARMACOKINETICS, SAFETY AND PRELIMINARY EFFICACY OF PAXALISIB IN NEWLY DIAGNOSED ADULT PATIENTS WITH UNMETHYLATED GLIOBLASTOMA (GBM)
Authors: Patrick Y Wen, John de Groot, James Battiste, Samuel Goldlust, Denise Damek, Benjamin Ellingson, James Garner, John Friend, Jeremy Simpson, Alan Olivero, Timothy Cloughesy
Journal: Neuro-Oncology (2022)

Abstract NCT03522298 was an open-label, multi-center, 2-stage trial designed to establish the maximum tolerated dose (MTD) for once-daily (QD) paxalisib dosing (Stage 1), then evaluate pharmacokinetics(PK) and safety and explore efficacy (Stage 2). Eligible patients had undergone surgical resection and chemoradiotherapy (EORTC 26981–22981/NCIC CE3), had a life expectancy of ³ 12 weeks and were progression free before starting adjuvant paxalisib. Stage 1 used a standard 3 + 3 dose-escalation design to determine the MTD. Stage 2 was a two-arm, open-label, expansion cohort with patients randomized 1:1 to receive paxalisib at the MTD under fed or fasted conditions. In both stages, treatment comprised daily paxalisib administered in continuous 28-day cycles, until disease progression or unacceptable toxicity. Patients (n = 30; 70.0% males, mean age 58.5 years, mean 3.75 months since diagnosis) received paxalisib for a mean duration of 99 (9-833) days. In Stage 1 (n = 9), an MTD of 60mg was established on the dose-limiting toxicities of hyperglycemia (n = 1) and stomatitis (n = 1) at 75mg. Paxalisib was well-tolerated with no unexpected safety signals. Adverse events (37%) or progressive disease (33%) were the primary reasons for treatment discontinuation. At the MTD, the PK profile was linear and dose-proportional with no differences in Tmax and elimination half-life under fed/fasted conditions. Ten patients underwent FDG-PET imaging, 8 (80%) had a decrease in FDG uptake on Day 3 and/or Day 7 in Cycle 1; 4 (40%) had a metabolic partial response. From date of diagnosis, progression free survival (mRANO, investigator review) was 8.6 months and overall survival was 15.7 months. Primary study outcomes (1) MTD of 60mg was established for QD dosing and (2) PK and safety were consistent with prior clinical experience. Preliminary efficacy signals were encouraging and further investigation of paxalisib 60mg QD in newly diagnosed and recurrent GBM is ongoing in a pivotal trial (GBM AGILE, NCT03970447).
SURG-01. DEVELOPMENT OF MURINE MODEL OF LASER INTERSTITIAL THERMOTHERAPY (LITT) FOR BRAIN TUMORS
Authors: Matthew Frain, Ghaidaa Ebrahim, Macaulay Tomdio, Hector Mendez-Gomez, Nagheme Thomas, Aida Karachi, Farhad Dastmalchi, Catherine Flores, Duane Mitchell, Frank Bova, Maryam Rahman
Journal: Neuro-Oncology (2022)

Abstract The objective of this study was to develop and test a murine system for delivery of laser interstitial thermotherapy (LITT). A system was built that allows for stereotactic placement of the laser into a mouse brain and real-time thermometry with a custom-made thermometer holder. Tissue heating curves for Laserglow Technologies 1064nm laser experiments testing tissue heating were performed by placing the laser in tissue and temperature monitoring via thermal probe. The laser was adapted for use with a stereotactic frame utilizing a system with a Hamilton syringe and a holder for consistent and precise placement of the thermal probe. The murine experiments were performed with C57BL/6 mice and samples were analyzed with H&amp;E staining. First, ideal laser output was established using chicken breast. Laser dial setting of 4.38 successfully achieved slow tissue heating while a setting of 4.43 and 4.50 accomplished it rapidly, reaching a thermal ablative temperature of 43C in three and a half minutes. Next, a system for laser placement into the murine brain using the stereotactic frame was built revealing that the thermometer probe would require a separate system for consistent and precise measurements of heating. A thermometer probe holder was designed and fashioned via trigonometric calculations that allowed for thermal monitoring within 3mm spacing during laser ablation. Mice were anesthetized and treated with laser ablation at laser output of 4.38 and 4.43. H&amp;E staining of the brain tissue demonstrated clear evidence of localized ablation identifiable by visible lesions on the H&amp;E slides. The successful development of the stereotactic system for acquisition of tissue heating data coupled with evidence of successful live brain tissue ablation in a murine model via LITT proves that our protocol is ready for research of therapeutic combinatorial effects on live tumor bearing mice.
CTNI-28. SYSTEMATIC REVIEW OF PHASE III TRIALS IN NEWLY DIAGNOSED GLIOBLASTOMA 2005-2021
Authors: Christoph Oster, Lazaros Lazaridis, Jonas Feldheim, Teresa Schmidt, Christoph Kleinschnitz, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Despite a plethora of studies since the EORTC/NCIC trial in 2005, glioblastoma (GBM) prognosis remains poor. We here identify and compare glioblastoma phase III trials in terms of efficacy and baseline characteristics in an attempt to summarize the experience of the past 16 years. METHODS A systematic literature search using PubMed and ClinicalTrials.gov was conducted to provide an overview of clinically relevant GBM phase III trials (years 2005-2021) of adult patients younger than 70 years of age. Search results were screened according to predefined inclusion criteria and either excluded or included in further analysis on study design, baseline characteristics, and survival results. RESULTS Eleven trials from the literature and clinical trial database fulfilled the search criteria. Among these trials, a total of three GBM phase III trials reported overall survival (OS) benefit, including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409) and CeTeG/NOA09 (NCT01149109). All three studies demonstrate similar hazard ratios, which translate into risk reduction of about 40%. Furthermore, low toxicity profile and mostly preserved quality of life were attributed to the treatments tested. Looking at the study designs, eight out of eleven trials were open label randomized trials, including all of the positive ones, and only three negative trials employed treatment blinding and a placebo control. Canonical baseline characteristics (extent of resection, age, gender, MGMT promoter methylation status) did not significantly differ between positive and negative trials. IDH mutation status was analyzed in only two trials, each showing a small percentage of IDH-mutant tumors only. CONCLUSION This analysis on GBM phase III trials conducted between 2005 and 2021 revealed that the majority of trials did not show a significant improvement in overall survival. CeTeG/NOA-09 and EF-14 are the only two studies with positive overall survival outcome since the EORTC/NCIC trial in 2005.
QLTI-26. INTEGRATION OF NEURO-ONCOLOGY CLINICAL PATHWAYS IN PROVIDENCE SOUTHERN CALIFORNIA CLINICAL RESEARCH NETWORK
Authors: Thomas Bott, Nanor Bozoyan, Trisha Babcock, Kristen Cushman, Akanksha Sharma, Naveed Wagle, Jose Carrillo, Tiffany Juarez, Santosh Kesari
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION ClinicalPath is an evidence-based oncology decision support and analytics tool for cancer care. ClinicalPath’s treatment recommendations are prioritized based on efficacy, toxicity, and cost by a nationwide committee of oncologists. The pathways are updated quarterly and are expected to speed the integration of new treatments into practice, standardize therapy, improve quality, and decrease cost. The pathway system also allows for local clinical trial mapping to promote clinical trial awareness and increase enrollment. ClinicalPath provides clinical pathways delivering personalized, evidence-based oncology guidance at the point of care. ClinicalPath’s network in North America serves more than 2,000 cancer physicians, within 54 practices in 31 states (15 academic medical centers, 29 hospital systems, and 9 community practices). Population: Our population is derived from multiple hospitals in Southern California within the Providence Health System. Methodology: Medical oncologists and Advanced Practice Providers received training on ClinicalPath before go-live. ClinicalPath was integrated into the Epic EHR in multiple Southern CA hospitals in a single month. RESULTS After 3 months of utilization within our Southern California region, 342 treatment decisions were made across all cancers, and 85.1% of cancer patients were treated on pathway. Of which, 7 treatment decisions were made within the neuro-oncology specialty, and 85.7% of those cancer patients were treated on pathway. CONCLUSION We successfully integrated and initiated ClinicalPath in a multiple hospital-affiliated community oncology clinical trial network. We are actively working across our Southern California Region to map locally available clinical trials to promote awareness and increase enrollment. Provider utilization and patient on-pathway rates are actively monitored and will be updated.
RADT-21. PATTERNS OF CARE AND OUTCOMES IN PEDIATRIC HIGH-GRADE GLIOMA PATIENTS ENROLLED IN THE PEDIATRIC PROTON/PHOTON CONSORTIUM REGISTRY
Authors: Anna Schramski, Torunn I Yock, Christine Hill-Kayser, Daniel J Indelicato, Arnold C Paulino, William Hartsell, Ralph Ermoian, Victor Mangona, Young Kwok, Iain MacEwan, Suzanne Wolden, Nicholas DeNunzio, Brion Shin, Subir Goyal, Bree Eaton
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Proton therapy (PRT) is increasingly utilized for pediatric brain tumors to reduce radiation associated treatment effects, but there is a lack of data evaluating PRT in pediatric high-grade glioma (pHGG). The purpose of this analysis is to report patterns of care and clinical outcomes for pHGG patients treated with PRT and enrolled in the prospective Pediatric Proton/Photon Consortium Registry (PPCR). METHODS Fifty-five pHGG participants treated with PRT were enrolled in the PPCR between Jan 2013 and Aug 2020. Progression free (PFS) and overall survival (OS) rates were calculated according to the Kaplan-Meier method. Univariate analyses were performed using Cox proportional hazards model with Firth’s penalization. RESULTS Among 49 patients with complete data, the median age was 12, the majority of patients were male (29), white (35), and non-Hispanic/Latino (41). Histology was grade IV (37), grade III (10) or HGG not specified (8). Resection was gross-total (24), near-total (4), or sub-total/biopsy (17). Six patients received prior RT. The median RT dose was 57.6 Gy (RBE) starting a median of 33.5 days after surgery. 39 patients received chemotherapy. The most common acute treatment toxicities were alopecia (36), fatigue (34), radiation dermatitis (22), nausea/vomiting (19), and headache (19). Median follow-up was 3.14 years (95% CI 1.62-3.97). At 3 years, PFS (95% CI) was 35.5% (20.8-50.6%) and OS was 55.6% (38-70%). Median PFS and OS are 1.6 (1.2-3.1) and 3.6 (1.6-NA) years, respectively. Higher radiation dose was associated with greater PFS (HR 0.97 (0.94-1.01), p=0.059) and OS (HR 0.95 (0.93-0.99), p=0.006). Patients ≤ 3 years at diagnosis (n=8) had 3-year PFS/OS of 72.9%/87.5% vs. 27.8%/49.4% for older patients (p=0.068/0.089, respectively). CONCLUSION These are the first published data with PRT for pHGG. Clinical outcomes are comparable to historical data with photon therapy. Additional analysis of treatment associated toxicity and patient quality-of-life are warranted.
CTNI-11. DEEP PHENOTYPING OF MULTI DRUG RESPONSES IN PATIENTS WITH GLIOMAS USING TUMOR-EMBEDDED MICRODEVICES
Authors: Pierpaolo Peruzzi, Christine Dominas, Sarah Blitz, E Antonio Chiocca, Patrick Y Wen, Oliver Jonas
Journal: Neuro-Oncology (2022)

Abstract The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor.
EXTH-42. DUAL ROLES OF PKR ORCHESTRATE ONCOLYTIC HSV SENSITIVITY AND ANTIGEN-SPECIFIC T CELL EXPANSION
Authors: Bangxing Hong, Upasana Sahu, Matthew P Mullarkey, Evan Hong, Pei Guangsheng, Yuanqing Yan, Yoshihiro Otani, Huihui Fan, Zhao Zhongming, Balveen Kaur
Journal: Neuro-Oncology (2022)

Abstract The host immune system has developed many mechanisms to defend against and clear virus infections, including PKR, cGAS-STING and TLR-MyD88 signaling pathways. Compromised anti-viral mechanisms in tumor cells allows for infection, replication and lysis by oncolytic viruses. However, compromised antiviral mechanisms, together with immune cells and the tumor microenvironment (TME), limit the sensitivity of oncolytic virus in tumor cells. We generated a novel oncolytic Herpes simplex virus, oHSV-shPKR which disables tumor-intrinsic PKR signaling. oHSV-shPKR significantly increases oHSV infection and lysis in both oncolytic virus-resistant and sensitive glioblastomas (GBMs). Infection of oHSV-shPKR in GBMs induces G2/M cell cycle arrest and inhibits tumor cell growth. oHSV-shPKR increases activation of antigen presentation cells through type I interferon signaling activation and its immune-stimulatory function to increase tumor-antigen specific CD8 T-cell expansion, including cytotoxic T lymphocytes. Preclinical studies showed that oHSV-shPKR intra-tumoral injection significantly inhibits human GBM patient derived xenograft (PDX) tumor growth in immune-deficient NSG mice and murine orthotopic GBM tumor growth in immunocompetent mice. The results demonstrate that the novel oHSV-shPKR has the potential to be used in clinical applications for both oHSV-resistant and sensitive GBM treatment.
NCOG-21. EFFECT OF PNEUMOCYSTIS JIROVECII PNEUMONIA PROPHYLAXIS ON HEMATOLOGIC TOXICITY IN PATIENTS RECEIVING CHEMORADIATION FOR PRIMARY BRAIN TUMORS
Authors: Lisa Arnold, Yoji Hoshina, Hyejung Lee, Benjamin Haaland, Howard Colman, Joe Mendez
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Management of diffuse gliomas often includes radiation plus concomitant and adjuvant temozolomide. Hematologic toxicities are common from this therapy. Patients frequently receive prophylaxis against pneumocystis jirovecii pneumonia (PJP) during chemoradiation; however, some PJP prophylaxis drugs have the potential to independently cause myelosuppression which could exacerbate the hematologic toxicities from chemoradiation requiring chemotherapy dose reduction or cessation. We seek to understand differences in the frequency of hematologic toxicities during chemoradiation when either trimethoprim/sulfamethoxazole (TMP/SMX) or pentamidine are used for PJP prophylaxis. METHODS This was a retrospective chart review of patients with primary brain tumors who were treated with first-time radiation and concurrent temozolomide between April 2014-August 2021 at the Huntsman Cancer Institute. Chi squared analysis was used to evaluate effect of choice of PJP prophylaxis on risk for neutropenia, lymphopenia, or thrombocytopenia within one month of finishing chemoradiation. Logistic regression was performed to evaluate the effect of PJP prophylaxis on the Common Terminology Criteria for Adverse Events (CTCAE) score for the lowest neutrophil, lymphocyte, and platelet count. RESULTS 217 patients were included in analysis. 144 patients received TMP/SMX, 69 received pentamidine, 1 received dapsone, and 3 received no prophylaxis at initiation of chemoradiation. Of patients who received TMP/SMX, 15.4% developed an absolute neutrophil count &amp;lt; 1,500 cells/µL while this occurred in 7.2% of patients receiving pentamidine (p=0.10). Platelet count &amp;lt; 100,000 occurred in 18.1% of patients who received TMP/SMX and 20.3% of patients who received pentamidine (p=0.70). Worst CTCAE scores for hematologic toxicities were similar between PJP prophylaxis groups. CONCLUSION Our study provides preliminary evidence that the type of PJP prophylaxis does not appear to significantly impact risk for hematologic toxicity in patients receiving radiation and concurrent temozolomide; however, there was a trend toward higher rates of neutropenia with TMP/SMX and larger analyses are needed to further evaluate these findings.
EPCO-31. AI-BASED PROGNOSTIC STRATIFICATION OF GLIOBLASTOMA USING H&amp;E-STAINED WHOLE SLIDE IMAGES
Authors: Bhakti Baheti, MacLean Nasrallah, Spyridon Bakas
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma is the most common and aggressive malignant adult brain tumor, with median overall survival (OS) of 14 months. Despite optimizations in the treatment regime and technological advancements, patient OS has remained unchanged for the last 20 years. Here we seek the prognostic stratification of glioblastoma patients, by virtue of distinct morphological patterns apparent in histopathology H&amp;E-stained whole slide images (WSI) alone. METHODS We selected 271 (ntraining/nhold-out-test= 216/55) frozen digitized tissue sections, at 10x magnification, of untreated primary glioblastoma (IDH-wildtype) adult cases from the TCGA-GBM collection, without history of previous glioma and with post-operative OS &amp;gt; 30 days. The median OS across cases was used to divide them into short- (&amp;lt; 324 days) and long- ( &amp;gt; 390 days) survivors, after excluding 5 percentiles of cases around this median. Each WSI was partitioned in non-overlapping 256x256 patches. A pre-trained VGG16 AI model automatically extracted a 512-dimensional feature vector from each patch. Dimensionality was reduced, from 512 to 8, using principal component analysis, and distinct groups of morphological patterns were identified with unsupervised clustering. The number of distinct groups was decided based on the silhouette coefficient, assessing goodness of clustering. The proportions of these patterns within each WSI, describing the tumor’s spatial heterogeneity, were used to distinguish between short- and long-survivors using gradient boosting. RESULTS We identified morphological patterns of 5 distinct groups, descriptive of cellularity differences as well as artifactual content. Quantification of these patterns’ proportions resulted in a classification accuracy of 72.72% (short- vs long-survivors). CONCLUSIONS We identified morphologic patterns within a WSI, associated with shorter and longer OS. These may allow the clinical neuropathologist to i) provide additional prognostic information gleaned during microscopic assessment to the treating team, and ii) suggest avenues for further biological investigations towards contributing to our mechanistic understanding and potentially treating of glioblastoma.
EXTH-25. EXPLOITING EPIGENETIC DYSREGULATION IN ISOCITRATE DEHYDROGENASE MUTANT GLIOMA VIA THE USE OF HISTONE DEACETYLASE INHIBITORS
Authors: Thomas Sears, Michael Drumm, Andrea Piunti, Craig Horbinski
Journal: Neuro-Oncology (2022)

Abstract Isocitrate dehydrogenase 1/2 mutations (IDHmut) define a unique subtype of glioma that exhibits profound epigenetic dysregulation through DNA and histone hypermethylation. Though IDHmutgliomas are less aggressive than their IDH wildtype (IDHwt) counterparts, these tumors are still incurable and are invariably fatal. New treatments are therefore needed. Histone deacetylase (HDAC) enzymes compose a class of epigenetic drug targets already used in the clinic to treat other malignancies, but their potential against gliomas, specifically IDHmutgliomas, have not been extensively studied. We previously showed that IDHwt gliomas are more sensitive than IDHwt gliomas to the cytotoxic and antiproliferative effects mediated by the FDA-approved HDAC inhibitor panobinostat, and that this sensitivity was associated with a greater increase in histone acetylation in IDHmut glioma cultures. Follow-up RNA-Seq showed that panobinostat more greatly affected gene expression in IDHmut glioma cells, with 1999 significant differentially expressed genes showing a 10% or greater change in gene expression in IDHmut cells compared to 388 genes for IDHwt counterparts. This included the known HDAC target and cell-cycle inhibitor CDKN1A, with panobinostat causing a 1.9-fold greater upregulation of CDKN1A in IDHmut cells than IDHwt cells (p= 0.045). In immunocompromised mice intracranially engrafted with IDHmut or IDHwt glioma, 15 mg/kg intraperitoneally-administered panobinostat was detectable after 6 hours within the intracerebral tumors via mass spectrometry at a concentration of 52.4 ng/g (150.1 nM), and extended the survival of IDHmut glioma-engrafted mice (Median: 4 days; Mean: 9.4 days), but not IDHwt glioma-engrafted mice (IDHmut: logrank p= 0.044; IDHwt: logrank p= 0.18). These results suggest that HDAC inhibition via panobinostat may be an effective therapy to treat IDHmutglioma patients. Ongoing studies, including ChIP-Seq, will determine specific sites of histone acetylation and HDACs that are responsible for the greater sensitivity of IDHmut gliomas to HDAC inhibition.
SURG-13. SYSTEMATIC REVIEW AND META-ANALYSIS OF IMPACT OF EXTENT OF RESECTION ON SURVIVAL ON GLIOBLASTOMA, IDH-WILDTYPE, WHO GRADE 4 (WHO 2021)
Authors: Ignacio Jusue-Torres, Jonathan Lee, Anand Germanwala, Terry Burns, Ian Parney
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma diagnostic criteria have been redefined with the 5th edition of WHO classification of tumors of the central nervous system. Glioblastomas are defined as IDH wildtype diffuse astrocytic glioma tumors with one of the following features: microvascular proliferation, or necrosis, or TERT promoter mutation, or EGFR gene amplification, or +7/-10 chromosome copy number changes. The aim of this study is to establish the impact of extent of resection in overall survival (OS) and progression free survival (PFS) in glioblastoma, IDH-wildtype (WT), WHO grade 4 (WHO 2021). METHODS Systematic literature search was performed using the following databases: PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and ClinicalTrials.gov to identify studies comparing OS and PFS after gross total resection (GTR) vs subtotal resection (STR) or biopsy for glioblastoma IDH-WT. Prognostic hazard ratios (HR) for OS and PFS were analyzed using a random-effects model. RESULTS We identified 1439 publications. Nine studies met inclusion/exclusion criteria. 788 patients underwent GTR out of 1818. The meta-analysis showed a significant increase in OS and PFS duration when undergoing GTR for glioblastoma IDH-WT with a median OS of 20 months 95% CI (17-25) compared to 12 months 95% CI (9-15) for STR or biopsy and a median PFS of 11 months 95% CI (9-12) for GTR compared to 7 months 95% CI (5-7) for STR or biopsy respectively. GTR showed a 49% significant reduction of mortality risk HR=0.51 95%CI (0.42-0.59) and a 44% significant reduction of progression risk HR=0.56 95%CI (0.41-0.71) compared to STR or biopsy. CONCLUSIONS This systematic review indicates that GTR may be associated with improved OS and PFS compared to STR or biopsy for Glioblastoma, IDH-WT, WHO grade 4 (WHO 2021). However, this is limited by variable study design and significant clinical and methodological heterogeneity among studies.